GENETIC-CONTROL OF THE INFLAMMATORY RESPONSE INDUCED BY OXIDIZED LIPIDS

The fatty streak begins with entrapment of apo-lipoprotein B (apoB)-co ntaining lipoproteins in the subendothelial space at susceptible sites in the arterial wall. Minimally oxidized low density lipoprotein (MM- LDL) induces endothelial cells to bind monocytes and produce message a nd protein for monocyte chemotactic protein-1 and macrophage colony-st imulating factor. In culture, human endothelial and smooth muscle cell s in arterial wall configuration sequester LDL, protecting it from ant ioxidants and giving rise to MM-LDL-like species. In mice, MM-LDL indu ces monocyte binding at susceptible aortic sites; the monocytes may th en differentiate Into macrophages that release reactive oxygen and act ive aldehydes, resulting in highly oxidized LDL leading to foam cell f ormation. Feeding mice an atherogenic diet induces expression of sever al inflammatory and oxidative stress genes, including serum amyloid A, which binds exclusively to HDL. This may contribute to a decrease in protective HDL levels seen in mice susceptible to fatty streak formati on.